Among drug candidates under evaluation/development, the problem of inadequate aqueous solubility is likely to be encountered with relatively high frequency. Inadequate aqueous solubility is a significant hurdle in formulating such compounds into a simple, isotonic, ready-to-inject aqueous solution. For oral administration, poor aqueous solubility of drugs can jeopardize the dissolution rate and bioavailability. Inadequate aqueous solubility reflects a less than desirable free energy of transfer from the solid phase to the aqueous solution. This may result from two causes: (a) polar compounds may exhibit low water solubility as a result of strong crystalline interaction due to intermolecular electrostatic attraction and/or hydrogen bonding in the crystal; or (b) lipophilic/hydrophobic compounds are likely to exhibit low water solubility due to unfavorable free energy of salvation by water. No matter the cause of the solubility problem, cyclodextrin complexation, micellar solubilization, cosolvency, and solutropy are four strategies that are commonly employed in circumventing the problem.
However, in general, a disadvantage of micellar solubilization is the large quantity of surfactant required to provide the several orders of magnitude
increases in solubility often desired. In addition, surfactant toxicity at high concentrations, particularly hemolysis, is a well-documented problem. The rapid reversibility of solubilization is another difficulty in the use of micellar solution as an approach for parenteral or oral route.
Oftentimes, non-aqueous solvents can effectively dissolve the drugs with inadequate aqueous solubility. For example, carbamazepine solubility in propylene glycol is about 310 fold of carbamazepine aqueous solubility. However, the toxicity of the non-aqueous solvents is a major concern. A 40% propylene glycol/water cosolvent system is near the upper limit in terms of its organic solvent composition for physiological compatibility. Based on metabolic and toxicological data, the WHO has set an acceptable daily intake of propylene glycol at up to 25 mg/kg body weight. Additionally, the solubility enhancement generally is significantly reduced in the mixture of non-aqueous solvent and water, compared to non-aqueous solvent alone.
The term “solutropy” was introduced to describe solubilization by the addition of a large amount of a second solute in both aqueous and nonaqueous solvents. The solubility enhancement either via solvent structure modification or via chemical complexation has been demonstrated in pharmaceutical applications. The following are the examples of hydrotropes commonly used in the pharmaceutical industry: nicotinamide, sodium salts of benzoic, naphtholic, and nicotinic acids, urea, sorbitol, fructose, sodium salicylate, sodium glycinate, and gentisate sodium. Toxicity of these hydrotropes, however, is a major concern. Furthermore, the solubility enhancement is compound-dependent and only modest enhancement can be expected using the hydrotrope approach.
Pharmaceutical applications of cyclodextrins have been considered for over 30 years. Cyclodextrins are cyclic oligosaccharides composed of 6-8 dextrose units (α-, β-, and γ-cyclodextrins, respectively) joined through 1-4 bonds. Because the interior of these molecules are relatively lipophilic and the exterior relatively hydrophilic, they tend to form inclusion complexes.
Safety is a major issue with any new material. Two of the parent cyclodextrins, i.e., α- and β-cyclodextrins, are known to be parenterally unsafe due to severe nephrotoxicity. However, α- and β-cyclodextrins have been used orally in both food products and in various approved pharmaceuticals. Other than the safety issue, low aqueous solubility is another drawback to using the parent cyclodextrins, which is especially true for β-cyclodextrin; the ring cavity for α-cyclodextrin is simply too small to encapsulate the drug molecules, in most cases.
Modification of the parent cyclodextrins to improve safety while maintaining the ability to form inclusion complexes with various substrates has been the goal of numerous research groups. The most significant cyclodextrin derivatives are the following: hydroxypropyl β-cyclodextrin, glucuronylglucosyl β-cyclodextrin, sulfobutylether β-cyclodextrin, and methylated β-cyclodextrin. These modified cyclodextrins and parent cyclodextrins provide have assisted formulators in overcoming solubility problems of poorly water-soluble drugs in various applications, i.e., parenteral, oral, buccal, ophthalmic, nasal, dermal, rectal, and pulmonary routes. While several cyclodextrins have been approved for use in pharmaceutical products, such as Sporanox (Janssen), Zeldox/Geodon (Pfizer), and Vfend (Pfizer), there is a need to find additional cyclodextrins to contribute to the formulators' arsenal. Although cyclodextrins are not the solution to all the solubility problems, they definitely have higher potential than other solubilization techniques.